Modulators of serotonin receptors

a serotonin receptor and receptor technology, applied in the field of serotonin receptor modulators, can solve the problems of side effects of breakthrough treatments, but not without side effects

Active Publication Date: 2005-04-14
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Modulators of serotonin receptors
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Examples

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example 1

Preparation of (±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

Step A. Preparation of N,N-diethyl-2-trifluoromethoxybenzamide

To a stirring solution of 2-trifluoromethoxybenzoic acid (3.6 g, 17.5 mmol, Avocado) in dry CH2Cl2 (150 mL) with DMF (0.5 mL) was added a 2M solution of oxalyl chloride in CH2Cl2 (17.5 mL) dropwise over 30 nin. The reaction was stirred for 4 h and then conc. in vacuo to a white solid. The solid was dissolved in CH2Cl2 (150 mL) and reacted with diethylamine (3.2 g, 43.8 mmol, Aldrich) the reaction was stirred for 16 h and then conc. in vacuo to a yellow solid. The solid was purified by radial chromatography (SiO2, 1:5, EtOAc:hexanes) to yield 4.3 grams (94%) of the product as a colorless oil. MS (ESI) 262 (M+H).

Step B. Preparation of N,N-diethyl-2-carboxaldhyde-6-trifluoromethoxybenzamide

To a stirring solution of N,N-diethyl-2-trifluoromethoxybenzamide (2260 mg, 8.7 mmol) and N,N,N′,N′-tetramethylethylenediamine (1410 mg, Aldr...

example 2

Preparation of (R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one hydrochloric acid salt

Step A. Preparation of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution of (±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one (432 mg, 1.6 mmol) in dry CH2Cl2 (10 mL) was added di-t-butyl dicarbonate (383 mg, 1.8 mmol, Aldrich). The reaction was stirred for 4 h and then conc. in vacuo to a white solid. The solid was purified by radial chromatography (SiO2, 1:10, EtOAc:hexanes). The compound was then separated by chiral HPLC using an OD column with 80% heptane with 0.1% diethylamine and 20% 1:1 MeOH:EtOH with 0.1% diethylamine to yield 181 mg of the R enantiomer and 217 mg of the S enantiomer as white solids. MS (ESI) 373 (M+H).

Step B. Preparation of (R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one Hydrochloride

To a stirring solution of N-...

example 3

Preparation of (S)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one hydrochloric acid salt

Prepared according to procedures described in Example 2 with substitution of N-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2, 1-a] isoindol-6(2H)-one for N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one at Step B. MS (ESI) 309 (M−Cl).

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Abstract

The present invention provides modulators of serotonin receptors, pharmaceutical compositions containing such modulators and methods for treating various diseases, conditions and disorders associated with modulation of serotonin receptors such as, for example: metabolic diseases, which includes but is not limited to obesity, diabetes, diabetic complications, atherosclerosis, impared glucose tolerance and dyslipidemia; central nervous system diseases which includes but is not limited to, anxiety, depression, obsessive compulsive disorder, panic disorder, psychosis, schizophrenia, sleep disorder, sexual disorder and social phobias; cephalic pain; migraine; and gastrointestinal disorders using such compounds and compositions.

Description

BACKGROUND OF THE INVENTION The neurotransmitter / hormone serotonin (5-hydroxytryptamine, 5-HT) regulates many physiological processes via a group of at least 14 distinct receptors that are organized into 7 subfamilies (Hoyer, D., et al., Pharmacol. Rev., 46, 1994). The 5-HT2 subfamily is composed of the 5-HT2A, 5-HT2B, and 5-HT2C receptors as determined by gene homology and pharmacological properties. There exists a substantial correlation for the relationship between 5-HT2 receptor modulation and a variety of diseases and therapies. Prior to the early 1990's the 5-HT2C and 5-HT2A receptors were referred to as 5-HT1C and 5-HT2, respectively. The direct or indirect agonism or antagonism of 5-HT2 receptors, either selectively or non-selectively, has been associated with the treatment of various central nervous system (CNS) disorders including obesity, depression, schizophrenia and bi-polar disorders. In the recent past the contribution of serotonergic activity to the mode of action ...

Claims

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Application Information

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IPC IPC(8): A61P25/24C07D471/04C07D487/04C07D498/04C07D513/04
CPCC07D471/04C07D513/04C07D487/04A61P25/24
Inventor WACKER, DEAN A.ZHAO, GUOHUAKWON, CHETVARNES, JEFFREY G.STEIN, PHILIP D.
Owner BRISTOL MYERS SQUIBB CO
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